1. Field of the Invention
The invention in general relates to the synthetic process for 4,4-Disubstituted piperidines. More specifically, the present invention relates to a novel process for the synthesis of 4-aryl 4-acyl piperidine derivatives using indium metal. Still more specifically, the present invention relates to a novel process for the synthesis of 4-acetyl 4-phenyl piperidine and its salts using indium metal.
2. Description of Prior Art
Disubstituted piperidines have been a part of many investigational drug molecules (Wieslaw M. Kazmierski et. al., Journal of Medicinal Chemistry, 2011, 54, 3756). Representative example 4-acetyl 4-phenyl piperidine and its derivatives are extensively discussed in (Wieslaw M. Kazmierski et. al., Journal of Medicinal Chemistry, 2008, 51, 6538).
The biological properties and applications of 4-Acetyl-4-phenyl piperidine have been reported in prior art.                a. 4-Acetyl 4-phenyl piperidine as a novel chlorokojic acid derivative has been investigated for its cytotoxicity along with its antimicrobial and antiviral activities (MutluDilsizAytemir, BerrinOzcelik, European Journal of Medicinal Chemistry, 2010, 45, 4089).        b. Several derivatives of 4-acetyl 4-phenyl piperidine were synthesized and evaluated for analgesic activity by Z. S. Saify et al., ZeitschriftfuerNaturforschung, B: Chemical Sciences; vol. 54; nb. 10; (1999); p. 1327-1336.        c. 4-acetyl 4-phenyl piperidine has been part of the design and synthesis of Novel α1aadrenoceptor-selective dihydropyridine antagonists beneficial in the treatment of benign prostatic hyperplasia (DhanapalanNagarathnam et. al., Journal of Medicinal Chemistry, 1998, 41, 5320).        
In spite of such extensive applications of 4-acetyl 4-phenyl piperidine in the fields of investigation drugs and medicinal chemistry, the synthesis of 4-acetyl 4-phenyl piperidine has not been easy. Prior art synthetic schemes as disclosed herein below are fret with technical problems including very long and arduous synthetic schemes, use of hazardous chemical agents for synthesis, non-feasible reaction conditions and non-scalability of process inventions at the industrial level.
For example, 4-acetyl 4-phenyl piperidine has been made from its N-benzyl derivative by hydrogenation using palladium/hydrogen for debenzylation (Journal of Organic Chemistry; vol. 22; (1957); p. 1484, 1488) [FIG. 1—Prior Art].
The starting material, 1-benzyl 4-acetyl 4-phenyl piperidine has been synthesized from 1-benzyl 4-cyano 4-phenyl piperidine using methyl magnesium bromide in toluene/THF medium. (Teraoka, Takashi and Uno, Osamu, Jpn. KokaiTokkyoKoho, 2007119406) and using methyl lithium (Perrine, T. D., Journal of Organic Chemistry, 1957, 22, 1484) [FIG. 2-Prior Art].
Further, 1-benzyl 4-cyano 4-phenyl piperidine has been synthesized from                1. Phenyl acetonitrile and N-benzyl 2-chloro(2-chloroethyl)ethanamine using sodium hydroxide as base under PTC catalysis (Leng, Xiansheng et al., From Faming ZhuanliShenqingGongkaiShuomingshu, 1535967, 13 Oct. 2004.        2. Benzylamine and 4-hydroxy-2-(2-hydroxyethyl)-2-phenylbutanenitrile (Asano, Shigehiro and Ban, Hitoshi, Heterocycles, 75(1), 183-188; 2008).        3. Phenyl acetonitrile and N-benzyl 2-chloro(2-chloroethyl)ethanamine using sodamide in toluene (Pajouhesh, Hassan et al., PCT Int. Appl., 2008031227, 20 Mar. 2008).        4. Phenyl acetonitrile and N-benzyl 2-chloro(2-chloroethyl)ethanamine using sodium hydride in THF at 80 degrees (Tang, Haifeng et al., Bioorganic & Medicinal Chemistry Letters, 20(20), 6088-6092; 2010)        
Schematically presented in FIG. 3—Prior Art.
It is clear that the synthetic schemes represented in FIGS. 1, 2 and 3—Prior Art have several process steps, use hazardous chemicals like sodium hydride, sodamide, triflic anhydride, include non-feasible reaction conditions like very low temperature conditions (−30° C.) making industrial applicability and scalability difficult. Thus, there is a need for practical, safe, scalable synthetic method for the synthesis of 4-acetyl 4-phenyl piperidine or in general the 4-aryl 1,4-diacyl dihydropyridine group of compounds.
It is thus the principle objective of the present invention to disclose shorter synthetic scheme for 4-acetyl 4-phenyl piperidine, the steps of which are easy to adopt, do not use hazardous chemicals and unfavorable reaction conditions and are industrially scalable to produce considerable quantities of 4-acetyl 4-phenyl piperidine.
The principle objective mentioned herein above in general also encompasses the synthetic scheme for 4-aryl 4-acyl piperidine derivatives using indium metal.
The present invention fulfills the aforesaid objectives and provides further related advantages.